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Prospects for extending healthy life - a lot Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA, USA and Cambridge, UK Email: aubrey@sens.org MF site: http://www.methuselahfoundation.org/ Science site: http://www.sens.org/ Prize site: http://www.mprize.org/.
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Prospects for extending healthy life - a lot
Aubrey D.N.J. de Grey, Ph.D.
Chairman and CSO, Methuselah Foundation
Lorton, VA, USA and Cambridge, UK
Email: aubrey@sens.org
MF site: http://www.methuselahfoundation.org/
Science site: http://www.sens.org/
Prize site: http://www.mprize.org/
Out now: $17.79 at Amazon
Why I am doing this
Product of evolutionary nelect, not intent
Metabolism ongoingly causes “damage”
Damage eventually causes pathology
Pathology causes more pathology
How to make a car last 50 years
-- plan A
Gerontology Engineering Geriatrics
Metabolism Damage Pathology
Claim: unlike the others, the engineering approach may achieve a large extension of human healthy lifespan quite soon
Reasons for the engineering approach
Reasons for the engineering approach
Retarding aging: benefits modest
max
Reserve
frail
0
0
Age
Halving rate of damage starting in middle age
- doubles remaining healthspan
- raises total healthspan by maybe 20%
max
hard
Reserve
easy
frail
0
0
Age
Fixing half the damage starting in middle age
- doubles total healthspan
- raises remaining healthspan maybe 5-fold
Robust human rejuvenation (RHR)
Addition of 30 extra years of healthy life (and total life) to people who are already in middle age when treatment is begun
Ever-improving repair: better yet
max
very hard
Reserve
hard
easy
frail
0
0
Age
Fixing half the damage, then 3/4
- not as good as doing 3/4 first time…
- but better than doing 1/2 first time…
max
Reserve
frail
0
0
Age
Fixing half the damage, then 3/4, then 7/8….
- outpaces the so-far-unfixable damage…
- maintains healthspan indefinitely
Longevity escape velocity (LEV)
The rate at which rejuvenation therapies must improve (following the achievement of RHR) in order to outpace the accumulation of so-far-irreparable damage
(Phoenix & de Grey, AGE, in press)
Metabolism ongoingly causes “damage”
and
Damage eventually causes pathology
So….
Simulations of aging (and intervention) should simulate damage accumulation
Structural parameters
N_CAT: The number of damage categories each person has N_MECH: The number of mechanisms in each category
MECH_WEIGHTm: The contribution of a mechanism to a category
Fitting parameters
BASAL_M: The mean basal damage rate BASAL_SD: The standard deviation of the basal damage rate
BASAL_H: The homogeneity of basal damage rate in a single person EXP_M: The mean exponential damage rate
EXP_SD: The standard deviation of the exponential damage rate
EXP_H: The homogeneity of exponential damage rate in a single person
FATAL_M: The mean yearly challenge FATAL_SD: The standard deviation of the yearly challenge
Values set for each person at initialisation:
PB: Basal rate for the person: lognorm(BASAL_M, BASAL_SD)
PE: Exponential rate for the person: lognorm(EXP_M, EXP_SD)
MBc,m:Basal rate for each mechanism: lognorm(BASAL_M, BASAL_SD)*(1-BASAL_H) + PB*BASAL_H
MEc,m: Exponential rate for each mechanism: lognorm(EXP_M, EXP_SD)*(1-EXP_H) + PE*EXP_H
D_Mc,m : Cumulative damage for each mechanism: 0 D_Cc : Cumulative damage for each category: 0
Variables updated for each person at each time step (year):
Total damage: PD(t) = [SUM c=1..N_CAT] D_Cc(t) Damage increment: DI_Mc,m(t) = MBc,m + MEc,m*PD(t-1)
Cumulative damage: D_Mc,m(t) = DI_Mc,m(t) + D_Mc,m(t-1)
Cumulative category damage: D_Cc(t) = [SUM m=1..N_MECH] DI_Mc,m(t)
Fatality challenge: FATAL(t) = |norm(FATAL_M, FATAL_SD)|
If D_Cc(t) > FATAL(t) for any c, the person dies at age t
max
Reserve
frail
0
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Age
Fixing half the damage, then 2/3, then 3/4….
- still good enough…
- just like gravitational escape velocity
Reasons for the engineering approach
Problem 2:this is the pathology
Seven Deadly Things
No new type of damage identified since 1982!
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
R5 day 71
R4 day 71
R1 day 71
R1 day 36
R2 day 71
R5 day 20
R2 day 36
R5 day 36
R3 day 71
R3 day 36
R4 day 36
1
2
5
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15
Example: DGGE Results from Perchlorate-Reducing, Membrane Biofilm Reactors
Graveyards:
- are abundant in human remains…
- accumulate bones (which are not energy-rich)…
- do not accumulate oxysterols, tau etc...
- so, should harbour microbes that degrade them
- whose catabolic enzymes could be therapeutic
Steps to biomedical application
Isolate competent strains; select by starvation
Identify the enzymes (mutagenesis, chemistry, genomics)
Make lysosome-targeted transgenes, assay cell toxicity
Assay competence in vitro (more mutagenesis/selection)
Construct transgenic mice, assay toxicity in vivo
Assay competence in disease mouse models
Test in humans as for lysosomal storage diseases
Eventual organisational structure
Level 1: funding of up to $300k per year guaranteed for at least 3 years. (This is where we are now.) Selected SENS strands supported at entry level (1 project/strand, 1-2 FTEs/project)
Level 2: funding of $300k-$3m per year, three years. (This is where we will be when the Thiel pledge is fully matched.) Six SENS strands supported at minimal level (1-3 projects/strand, 1-3 FTE/project)
Level 3: funding of $3M-$20M per year guaranteed for at least five years. Grant applications solicited; 30-100 FTEs funded, across up to 30 projects
Level 4: funding of $20M-$100M per year, ten years. Physical facility (“Institute for Biomedical Gerontology”) set up (50-150 FTEs); extramural research support as in Level 3 (100-350 FTEs)
I offer no apology for using media interest in life extension to make the biology of ageing an exception to Planck’s observation that science advances funeral by funeral: lives, lots of them, are at stake.
de Grey 2005, EMBO Reports 6(11):1000
Out now: $17.79 at Amazon
